tbuckley/cabot-search huggingface dataset:
Association between germ-line HLA and immune-related adverse events.
Authors: Ning Jiang, Yue Yu, Dawei Wu, Shuhang Wang, Peiwen Ma, Huilei Miao, Yu Tang, Ning Li
Journal: Journal of Clinical Oncology (2022)

2658 Background: In recent years, great progress has been made in immune checkpoint inhibitors (ICIs), opening a new chapter for cancer treatment. However, accompanied by remarkable efficacy, immune-related adverse events (irAEs) also arose. Though some pilot studies have explored the possible factors that may influence the development of irAEs, the mechanism of irAEs remains unclear. Previous studies indicated a positive association between certain HLA types and irAEs. To uncover the relationship between irAEs and divergent HLA types, we initiated a large cohort study. Methods: We screened 626 patients who have been treated in the clinical research ward, Cancer Hospital of Chinese Academy of Medical Sciences. All participants included should be diagnosed with malignant tumors and have received at least 2 cycles of ICIs with complete security follow-up data in the original electronic medical records. The blood samples were collected before the first cycle of treatment. Sequencing libraries were generated using a customized panel. Six digit formatted HLA alleles were extracted from HLA-HD (v1.4.0) results for further analysis. Fisher-exact test was used to perform association analysis between HLA and different irAEs. To control the type I error, we introduce two external reference groups as well as the non-irAE control group. In addition, false discovery rate (FDR) correction was performed with the resulting p-values when comparing the HLA allele frequency between patients with irAEs and the MHC-han Chinese reference cohort. We also explored the relationship between zygosity of HLA genes, evolutionary divergence of HLA class I genotype (HED) and irAEs. Results: Of the 626 participants, 530 received at least 2 doses of ICIs. The median follow-up time was 10.3 months. 97% patients received anti-PD-1/PD-L1 treatment. Of all participants, 78% reported irAEs of any grade, with 10.2% reporting grade 3 and above irAEs. The occurrence of overall irAEs showed no significant difference between homozygous group and heterozygous group. We did not find any significant association between irAEs and HED. We found that some HLA types are associated with irAEs of different organs, including the significant association between HLA-DRB3*01:01 and thrombocytopenia (OR 3.48 (1.19,9.42), p = 0.011), HLA-DPB1*04:02 and hypokalemia/ hyponatremia (OR 3.44 (1.24,9.1), p = 0.009), leukopenia (OR 2.1 (0.92,4.8), p = 0.037) as well as anemia (OR 2.33 (1.0,5.41), p = 0.026), HLA-A*26:01 and bilirubin elevation (OR 2.67 (0.92,8.31), p = 0.037). Conclusions: IrAEs in specific organs and tissues may be associated with certain HLA types, while HLA heterogeneity have no significant influence on the happening of irAEs. More research is needed to explore the role of germline genetic changes in the risk assessment of irAEs, and potential therapies targeting irAE-inducing HLA types without influencing the anticancer effect may be considered to benefit the patients.
Developing and testing compassion‐based self‐help for people living with psoriasis
Journal: British Journal of Dermatology (2022)

Psoriasis is a chronic autoimmune disease that included scaly patches on the skin.The disease occurs in 2-3% of the population and may affect as many as 125 million people worldwide.There is an increased risk of depression in people with psoriasis.In this UK study, we developed and tested a compassion-based self-help intervention aimed at reducing feelings of distress and improving the quality of life of people with psoriasis.We developed two booklets and audio-recordings of compassion-based self-help exercises.One of the booklets set out to increase people's ability to self-sooth.The other booklet set out to help people develop mindfulness, or the ability to pay attention on purpose, in the present moment, and without judgement.It focused on mindful breathing.We wanted to find out whether the use of the booklets over a 4-week period helped to reduce feelings of shame and thoughts of self-criticism, and lead to improvements in quality of life.There were 130 people with psoriasis who participated in the study.Half received the guided self-soothing self-help and half received the guided mindful breathing self-help.In total, 92 people completed the study and the majority reported finding the materials useful.Questionnaires administered before and after use of the materials showed that there were reductions in feelings of shame and improvements in their quality of life.These findings indicate that psychological support aimed at increasing compassion towards oneself can be useful in reducing feelings of distress associated with psoriasis.
LGG-50. Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling
Authors: Corina Anastasaki, Jit Chatterjee, Olivia Cobb, Suzanne Scheaffer, Shilpa Sanapala, Amanda Costa, Anna Wilson, Joel Garbow, Fausto Rodriguez, David Gutmann
Journal: Neuro-Oncology (2022)

Abstract A major obstacle to identifying improved treatments for pediatric low-grade brain tumors (gliomas) is the inability to reproducibly generate human xenografts. To surmount this barrier, we leveraged human induced pluripotent stem cell (hiPSC) engineering to generate low-grade glioma (LGG) lesions representing the two most common pediatric pilocytic astrocytoma-associated molecular alterations, NF1 loss and KIAA1549:BRAF fusion. Using hiPSCs, we identified the susceptible cells of origin for these tumors, and demonstrated that the resulting tumors retain LGG histologic features for at least 6 months in vivo. Finally, this platform enabled the successful long-term growth of patient-derived pLGGs in vivo. Taken together, these avatars establish tractable experimental humanized platforms to elucidate the pathogenesis of childhood brain tumors.
Retzius-sparing robot-assisted radical prostatectomy in high-risk prostate cancer patients
Authors: P. Dell'Oglio, S. Tappero, M. Longoni, C. Buratto, P. Scilipoti, S. Secco, A. Olivero, M. Barbieri, E. Palagonia, G. Napoli, E. Strada, G. Petralia, D. Di Trapani, A. Vanzulli, A.M. Bocciardi, A. Galfano
Journal: European Urology (2022)
Is cure possible for breast cancer metastatic to the liver?
Authors: Rene Adam, David Badrudin, Marc Antoine Allard, Nicolas Golse, Ayhan Ulusakarya, Daniel Cherqui, Antonio Sa Cunha, Eric Vibert, Daniel Azoulay, Oriana Ciacio, Gabriella Pittau, Angelica Lucchese, Pascal Hammel, Maite Lewin, Sylvie Giacchetti
Journal: Journal of Clinical Oncology (2022)

1099 Background: Metastatic breast cancer (MBC) is a lethal disease and is generally only amenable to systemic treatment. Although increasingly recommended on selected patients, local treatments, and particularly surgery, are seldom used in the therapeutic armamentarium for MBC and their long-term survival benefit is unknown. We hypothesized that combining surgery to systemic treatment for selected patients with breast cancer liver metastases could lead to long-term survival or even an option of cure. Methods: A retrospective study of prospectively gathered data from a surgical series of liver resections for MBC was conducted. Patients with no or limited and stable extra-hepatic disease were offered surgery after multidisciplinary discussion, if the liver metastases were responding to systemic treatment and were amenable to complete macroscopic resection. Five- and ten-year actual survivors were identified and their characteristics were explored. Results: From 1984 to 2020, 207 female patients underwent liver resections for MBC in our institution. There was no postoperative mortality. Postoperative complication rate was 23.3% and liver-specific complication rate was 19.0%. There was a total of 48 repeat hepatectomies. Median disease-free interval between initial breast cancer and liver metastasis was 36 ± 90.1 months. There was a median of 2 ± 1.8 liver metastases at diagnosis with a median size of 33.0 ± 18.3 mm and 73.1% of patients had radiological response before resection. Five- and ten-year overall survivals (OS) as well as 5- and 10-year disease-free survivals (DFS) were 39.6% and 12.7% as well as 14.2% and 6.4%, respectively. Median OS was 44.0 ± 47.2 months in the whole series. Focusing on the 5- and 10-year survivors, median OS were 89.5 ± 44.7 months and 144.0 ±42.6 months, respectively. In the 10-year survivors’ group, median DFS was 98 ±62.3 months. Observed survivals in this study underestimate true actual survivals owing to censoring of patients lost to follow-up. Conclusions: Long-term survival (≥ 5 years) as well as a curative perspective (≥ 10 years survival) are achievable for selected patients with breast cancer liver metastases by combining surgery to systemic treatment. Considering the recent improvements in the results of systemic treatments, introducing surgical resection in the treatment sequences of MBC could play an even more beneficial role.
A phase II study (TACTI-002) in first-line metastatic non–small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: Updated results from a PD-L1 unselected population.
Authors: Enriqueta Felip, Margarita Majem, Bernard Doger, Timothy Dudley Clay, Enric Carcereny, Igor Bondarenko, Julio Antonio Peguero, Manuel Cobo-Dols, Martin Forster, Grygorii Ursol, Gema García Ledo, Laia Vilà, Matthew Krebs, Wade Thomas Iams, Christian Mueller, Frederic Triebel
Journal: Journal of Clinical Oncology (2022)

9003 Background: Eftilagimod alpha (E) is a soluble LAG-3 protein binding to a subset of MHC class II molecules to mediate antigen presenting cell (APC)/CD8 T-cell activation. Stimulation of the APCs and subsequent T cell recruitment with E may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We hereby report results of the extended first-line non-small cell lung carcinoma (NSCLC) cohort of the TACTI-002 (“Two ACTive Immunotherapies”) phase II trial. Methods: Pts with untreated metastatic NSCLC, unselected for PD-L1 expression were recruited. Objective response rate (ORR) by iRECIST was the primary endpoint (EP) and secondary EPs include ORR by RECIST 1.1, tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS) and exploratory biomarker. Pts received 30 mg E SC q2w for 8 cycles (1 cycle= 3 weeks) and then q3w for up to 1 year with P (200 mg IV q3w for up to 2 years). Imaging was done every 8 weeks. PD-L1 was assessed centrally. This has been approved by relevant CAs, ECs, and IRBs. Results: From Mar 2019 to Nov 2021 114 pts were enrolled. Median age was 67 years (44-85) and 74% were male. ECOG PS was 0 and 1 in 37% and 63% of pts, respectively. Pts presented squamous (35%) or non-squamous (62%) NSCLC with 88% of pts at stage IV at the time of study entry. All PD-L1 subgroups were represented (Table). Pts received median 6.0 (range 1–35) P and 7.0 (1-22) E administrations. 19 (17%) pts discontinued treatment due to adverse events (AEs). The most common (≥15%) AEs were dyspnea (33%), asthenia (30%), decreased appetite (22%), cough (20%), anemia (20%), fatigue (19%), pruritus (18%), constipation (17%) and diarrhea (15%). At data cut-off (Jan 2022), 75 pts with a minimum follow-up of 6 months were evaluated for efficacy. ORR (iRECIST) was 37.3% in the ITT and 41.8%% in the evaluable pts assessed by local read. DCR 73.3% was reported. Response rate for squamous and non-squamous pathology were 33.3 % and 40.3 %, respectively. Results according to RECIST 1.1 were comparable. Responses were observed in all PD-L1 subgroups (Table). 24/28 (86%) responses were already confirmed while median duration of response was not yet reached (5 events). Conclusions: E + P is safe and shows encouraging antitumor activity in first-line metastatic NSCLC patients unselected for PD-L1, warranting further investigation. Clinical trial information: NCT03625323. [Table: see text]
DIPG-24. Neurological symptom improvement after re-irradiation in patients with diffuse intrinsic pontine glioma (DIPG): A retrospective analysis of the SIOP-E-HGG/DIPG project.
Authors: Lara Chavaz, Geert O Janssens, Stephanie Bolle, Henry Mandeville, Monica Ramos-Albiac, Karen van Beek, Helen Benghiat, Bianca Hoeben, Andres Morales La Madrid, Clemens Seidel, Rolf-Dieter Kortmann, Darren Hargrave, Lorenza Gandola, Emilia Pecori, Dannis G van Vuurden, Veronica Biassoni, Maura Massimino, Christof Kramm, Andre O von Bueren
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: To investigate the spectrum of neurological triad improvement in patients with diffuse intrinsic pontine glioma (DIPG) treated by re-irradiation (re-RT) at first progression. METHODS: Re-analysis of the SIOP-E retrospective DIPG cohort by investigating clinical benefits after re-RT with focus on the neurological triad. Patients were divided as "responding" or "non-responding" to re-RT. To assess the interdependence between patients’ characteristics and clinical benefits we used a Chi-Square or Fisher’s Exact test. Survival according to clinical response to re-RT was calculated by the Kaplan-Meier method. RESULTS: As earlier reported, 77% (n = 24/31) of patients had any clinical benefit after re-RT. Among 25/31 well documented patients, 44% (n=11/25) had improvement in cranial nerve palsies, 40% (n=10/25) in long-tract signs, 44% (11/25) in cerebellar signs. Clinical benefits were observed in at least 1, 2 or 3 out of 3 symptoms of the DIPG triad, in 64%, 40% and 24% respectively. Patients irradiated with a dose ≥ 20 Gy versus &amp;lt; 20 Gy may improve slightly better with regards of ataxia (67% versus 23%; P-value = 0.028). The survival from the start of re-RT to death was not different between responding and non-responding DIPG patients (P-value = 0.871). CONCLUSION: A median re-irradiation dose of 20 Gy provides a neurological benefit in two-third of patients with an improvement of at least one symptom of the triad. DIPG patients receiving ≥20 Gy appear to improve slightly better with regards of ataxia, however we need more data to determine whether dose escalation up to 30 Gy provides additional benefit.
Fecal microbiota transplantation followed by anti–PD-1 treatment in patients with advanced melanoma.
Authors: Wilson H. Miller, Bertrand Routy, Rahima Jamal, D. Scott Ernst, Diane Logan, Khashayar Esfahani, Karl Belanger, Arielle Elkrief, Rejean Lapointe, Pamela Thebault, Mayra Ponce, Seema Nair Parvathy, Meriem Messaoudene, Micheal Silverman, Saman Maleki, John Gordon Lenehan
Journal: Journal of Clinical Oncology (2022)

9533 Background: The gut microbiome has been shown to be a biomarker of response in patients (pts) with melanoma. Strategies to modify the microbiome are currently being investigated. We report the effects of Fecal Microbiota Transplantation (FMT) on safety and anti-PD-1 response in pts with melanoma from a phase I trial (NCT03772899). Methods: 20 pts with advanced melanoma with RECIST-evaluable disease, without prior anti-PD-1 treatment for advanced disease, were recruited from 3 Canadian academic centers. Pts with ECOG &gt; 2, autoimmune diseases, immunosuppression or unstable brain metastases were excluded. Pts received 80-100 g of healthy donor stool via oral capsules and were treated with anti-PD-1 one week later. The primary objective was safety of combining FMT with anti-PD-1 therapy. Objective response rate (ORR) by RECIST 1.1 and correlative studies were secondary objectives. Flow cytometry and multiplex ELISA were performed on pts blood samples. Avatar mice were transplanted with stool samples obtained from participants on the trial before and after FMT. Mice were subsequently implanted with B-16 or MCA-205 tumors and received anti-PD-1 antibodies. Results: Median age was 75.5 years, 12 (60%) were male, 18 (90%) had stage 4 disease, and 5 (25%) pts harbored a BRAF mutation. Median follow-up was 11.2 months. FMT-related adverse events included grade 2 diarrhea (2 pts) and hypophosphatemia (1 pt), and 13 pts (65%) experienced grade 1 gastrointestinal toxicities. Grade 3 immune-related adverse events (irAE) were one each of myocarditis, nephritis, and fatigue. Anti-PD-1 therapy was discontinued for toxicity in 2 (10%) pts. No unexpected irAE or death on treatment occurred. ORR was 65% (13/20), of which 3 were CR. Clinical benefit rate (includes SD lasting &gt; 6 months) was 75% (15/20). Median PFS was not reached, and one pt died from their disease. Translational analyses demonstrated upregulation of IL-17 post-FMT in responders, which correlated with upregulation of the frequency of Th17 cells in peripheral blood. In parallel, murine experiments showed that feces from pts pre-FMT did not sensitize tumors to anti-PD-1. In both tumor models, only feces obtained post-FMT from responders restored anti-PD-1 efficacy in mice, providing strong support that FMT contributed to the anti-tumor response observed in pts. Conclusions: FMT followed by anti-PD-1 treatment in melanoma pts undergoing therapy is safe and may lead to improved anti-tumor responses that can be reproduced in tumor mouse models. The gut microbiome plays an important role in responses to anti-PD-1 in patients with advanced melanoma, paving the way for future microbiome-based interventions. Clinical trial information: NCT03772899.
The updated EAU prognostic factor risk groups overestimate the risk of progression in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin
Authors: N. Lobo, P.J. Hensley, K.K. Bree, G.M. Nogueras-Gonzalez, N. Navai, C.P. Dinney, R.J. Sylvester, A.M. Kamat
Journal: European Urology (2022)
Reverse Liver Spleen Uptake on [68Ga]Ga-PSMA-11 PET/CT
Authors: Sofiullah Abubakar, Khulood Al Riyami, Anjali Jain, Vipin Jayakrishnan, Naima Tag
Journal: Clinical Nuclear Medicine (2022)

Abstract An 80-year-old man underwent [ 68 Ga]Ga-PSMA-11 PET/CT for staging of high-risk prostate cancer. Homogeneously increased liver uptake, more than 3-fold the splenic uptake, was seen. There was no hepatic lesion evident on CT. A higher liver to splenic uptake is more typical of some 18 F-labeled PSMA PET/CT but unusual in 68 Ga-labeled PSMA PET/CT scan. Further evaluation revealed a history of impaired renal function, bilateral renal atrophy, relatively decreased renal uptake of [ 68 Ga]Ga-PSMA-11, and prominent bowel activity. We concluded that impaired renal function and subsequent poor excretion resulted in increased hepatic excretion, hence the unusual increased homogeneous hepatic uptake.
HDAC inhibitor Chidamide, but not romidepsin, synergizes with humanized PD1 antibody to enhance T-cell chemokine expression and augment IFN-gamma response in NK-T-cell related lymphoma: A preclinical study.
Authors: Tingyu Wen, Fei Ma, Peng Liu
Journal: Journal of Clinical Oncology (2022)

e14568 Background: The incidence of NK-T cell lymphoma (NKTL) in Asia is significantly higher than that in European and American countries. The median survival time of EKTL is only 8-12 months, and the 5-year overall survival rate is still less than 30%. New therapies or combinations are warranted. Methods: The murine NKTL cell line EL4 and RMA were used to establish cell line xenograft models in transgenic humanized PD1 mice. Different dosages or sequential HDAC inhibitors were combined with humanized PD1 antibody in vivo to test whether the synergistic effect is existing. RNA-seq, qPCR, and IHC were performed to illustrate the potential mechanisms. Three NTKL patients who were treated with hPD1 and Chidamide in clinical were recorded in this study. Results: Romidepsin combined with hPD1 antibody is superior to hPD1 antibody alone in the treatment of two NKTL CDX models (EL4 and RMA), but it is similar with romidepsin single agent, either in different dosages or sequence. However, Chidamide combined with hPD1 antibody significantly inhibits the tumor growth compared to single agents in these two pre-clinical models. RNA-seq reveals Chidamide synergizes with humanized PD1 antibody to enhance T-cell chemokine expression, augment IFN-gamma response and increase CD8 T cell infiltration. String PPI analysis and ingenuity pathway analysis suggest IFN-gamma is the hub upstream regulator in the combination. On the contrary, the romidepsin combinations decrease the activity of T cell immune responses and the function of immune cell migration. The expression of IFN-gamma gene set signatures is decreased in the romidepsin combination. Three NKTL patients who received PD1 antibody and Chidamide are showed promising efficacy, and the progression-free survival is 26+ months, 8 months, and 9+ months respectively. Conclusions: Different HDAC inhibitor shows different combination effects with immunotherapy. Chidamide combination shows a synergistic effect with immunotherapy by enhancing INF-gamma response, but romidepsin combination antagonizes this effect significantly.
BBP-711 for the treatment of hyperoxaluria: A first-in-human, randomized, placebo-controlled safety, tolerability, pharmacokinetic, and pharmacodynamic study in healthy adult volunteers
Authors: J.C. Fox, S.H. Adler, S. Rao, R. Sukhun, L. Lee, C. Henry, J. Lafountaine, U. Sinha, T. O'Reilly
Journal: European Urology (2022)
Phase II trial of efficacy, safety and biomarker analysis of sintilimab plus anlotinib for patients with recurrent or advanced endometrial cancer
Authors: Wei Wei, Xiaohua Ban, Fan Yang, Jibin Li, Xiaqin Cheng, Rong Zhang, Xin Huang, Yongwen Huang, Qiaqia Li, Ya Qiu, Min Zheng, Xiaofeng Zhu, Jundong Li
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Although co-inhibition of the angiogenesis and programmed death 1 (PD-1) pathways is proposed as an effective anticancer strategy, studies in Chinese patients with endometrial cancer are sufficient. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor affecting tumor angiogenesis and proliferation; sintilimab is an anti-PD-1 monoclonal antibody. Methods This was a phase II trial using Simon’s two-stage design. This study enrolled patients with endometrial cancer who had progressed after platinum-based chemotherapy. Sintilimab 200 mg was administered intravenously on day 1 every 3 weeks, and anlotinib 12 mg was administered on days 1–14 in a 21-day cycle. The primary endpoint was the objective response rate (ORR) using the immune-related Response Evaluation Criteria in Solid Tumors criteria. Immunohistochemistry and whole-exome sequencing were used as correlative investigations. Results Between November 2019 and September 2020, 23 eligible patients were enrolled. The ORR and disease control rates were 73.9% (95% CI, 51.6 to 89.8) and 91.3% (95% CI, 72.0 to 98.9), respectively, with 4 complete and 12 partial responses. With a median follow-up of 15.4 months (95% CI, 12.6 to 18.3), the median progression-free survival was not reached, and the probability of PFS &gt;12 months was 57.1% (95% CI, 33.6 to 75.0). Exploratory analysis revealed that mutations in the homologous repair pathway showed a trend for higher ORR (100% vs 0%, p=0.07). Treatment-related grade 3/4 adverse events were observed in 50.0% of the patients. Conclusions Sintilimab plus anlotinib demonstrated robust therapeutic benefits with tolerable toxicity in endometrial cancer. Trial registration number NCT04157491 .
Chemotherapy enhanced by ultrasonic cavitation in prostate cancer by opening the blood-prostate barrier
Authors: J. Lu, J.D. He, H.Z. Xia, D.C. Yang, W. He, X.H. Zhu, Y. Yan, Z.N. Liu, T. Liu, J.L. Yang, S. Tan, J. Jiang, X. Hou, H.L. Gao, L. Ni
Journal: European Urology (2022)